Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism

Abstract

Cyclooxygenase (COX) ‐2 is a key enzyme in the conversion of arachidonic acid (AA) to prostanoids . Inhibition of COX‐2‐dependent prostanoids by nonsteroidal anti‐inflammatory drugs (NSAIDs) (both traditional(t) and selective for COX‐2, named coxibs) is involved in their efficacy in affecting pain and inflammation and in reducing the recurrence of colorectal polyps. However, the use of tNSAIDs and coxibs is associated with a small but consistent increase of cardiovascular (CV) risk which is believed to be due to the reduction of the biosynthesis of endothelial COX‐2‐dependent prostacyclin (PGI 2 ) . Novel knowledge on the biology of COX‐2 show that endocannabinoids may be the substrate for the COX‐isozyme. Endocannabinoids and endocannabinoid‐derived products of COX‐2‐mediated oxidative metabolism serve a variety of regulatory functions. Interference with endocannabinoid metabolism by NSAIDs might contribute to their pharmacological effects. Key Concepts: COX‐2 is overexpressed in inflammation and cancer mainly through posttranscriptional mechanisms involving stabilisation of its mRNA. Enhanced cytoplasmic levels of RNA stability factors, such as HuR, and reduced levels of microRNAs govern COX‐2 mRNA stability and translational efficiency. The constitutive expression of COX‐2 in endothelial cells plays an important role in cardiovascular homoeostasis through the generation of prostacyclin. COX‐2 is the target of NSAIDs, traditional and coxibs, thus leading to therapeutic effects and cardiovascular hazard, in some individuals. The major mechanism of action of NSAIDs is through the inhibition of the conversion of AA to biologically active prostanoids. Novel knowledge on the biology of COX‐2 shows that the activity of the COX‐isozyme may be involved in the generation of novel biologically active lipid mediators through the metabolism of endocannabionids. COX‐2 might affect endocannabinoid tone by contributing to its reduction. Endocannabinoids activate cannabinoid receptors to serve a variety of regulatory functions. These novel actions of COX‐2 may suggest their contribution to the therapeutic effects of NSAIDs. The (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are inactive to inhibit the metabolism of AA by COX‐2, are potent substrate‐selective inhibitors of endocannabinoid oxygenation. The discovery of these novel effects of (R) enantiomers of NSAIDs opens the way to develop novel analgesic drugs based on this mechanism of action.